PROJECT SUMMARY ? Administrative Core Children with NUP98-rearranged acute leukemias demonstrate a poor response to conventional therapy and are associated a high rate of relapsed disease and poor outcome. These fusions account for approximately 10% of children with AML, yet our overall understanding of the molecular consequences of fusion oncoprotein expression has been limited in part by a paucity of suitable model systems, which in turn has prevented the development of rational and targeted therapeutic approaches. The overarching goals of the FusOnC2 Center for Experimental and Preclinical Modeling of NUP98 Acute Leukemia are to understand the mechanistic basis of leukemogenesis and develop and translate new, more effective therapeutic approaches for this form of leukemia. These goals are to be accomplished in four research projects utilizing three core facilities, Administrative, Genome Editing and Chemical Biology in four academic research centers: St Jude Children?s Research Hospital, Memorial Sloan Kettering Cancer Center, Dana Farber Cancer Institute, and City of Hope. The projects will perform experimental modeling of NUP98 and concomitant genomic lesions in mouse and human models and test activity of chemical agents (Project 1); examine the role of NUP98 fusions on transcriptional and chromatin complex assembly (Project 2); examine the role of phase separation in transcriptional deregulation in leukemogenesis (Project 3); and develop and test new small molecule and degrader therapeutic approaches (Project 4). The Center will be highly interactive and collaborative, with interactions between projects and cores synergizing to accelerate the pace of discovery and translation for this high risk form of leukemia. The Administrative Core will be located at St Jude and comprise an Executive Management Team, administrative, grants and project management assistance. The Administrative Core will facilitate administrative support for progress meetings, on site and FusOnC2 meetings, financial management, internal and external data sharing and website, ensure compliance with all institutional, state and federal regulations, and coordinate periodic reporting of research activity to the NIH.